Systematic assessment of process analytical technologies for biologics.

The application of process analytical technology (PAT) for biotherapeutic development and manufacturing has been employed owing to technological, economic, and regulatory advantages across the industry. Typically, chromatographic, spectroscopic, and/or mass spectrometric sensors are integrated into upstream and downstream unit operations in in-line, on-line, or at-line fashion to enable real-time monitoring and control of the process. Despite the widespread utility of PAT technologies at various unit operations of the bioprocess, a holistic business value assessment of PAT has not been well addressed in biologics. Thus, in this study, we evaluated PAT technologies based on predefined criteria for their technological attributes such as enablement of better process understanding, control, and high-throughput capabilities; as well as for business attributes such as simplicity of implementation, lead time, and cost reduction. The study involved an industry-wide survey, where input from subject matter industry experts on various PAT tools were collected, assessed, and ranked. The survey results demonstrated on-line liquid Chromatography (LC), in-line Raman, and gas analysis techniques are of high business value especially at the production bioreactor unit operation of upstream processing. In-line variable path-length UV/VIS measurements (VPE), on-line LC, multiangle light scattering (MALS), and automated sampling are of high business value in Protein A purification and polishing steps of the downstream process. We also provide insights, based on our experience in clinical and commercial manufacturing of biologics, into the development and implementation of some of the PAT tools. The results presented in this study are intended to be helpful for the current practitioners of PAT as well as those new to the field to gauge, prioritize and steer their projects for success.

Good design practices for an integrated containment and production system for advanced therapies.

Advances in molecular biology and the possibility of differentiating stem cells have opened up new scenarios in therapies that use progenitor or variously differentiated cells. Regardless of the choice of the system, designing a plant for producing advanced therapies requires a clear understanding of the final objective (the product), taking into account all the regulatory, environment, process, risk assessment, asepsis, and validation aspects involved until its implementation. Good Manufacturing Practice (GMP) compliant procedures are a prerequisite for cell production in clinical application, and clean rooms are zones for producing cell therapies. Clean rooms for clinical application require high running and maintenance costs and need trained operators and strict procedures to prepare the rooms and the people involved in the processes. While today production mainly occurs in open systems (clean rooms), there is evidence of processes in closed systems (isolators). The isolator is a Grade A aseptic closed system that requires a controlled environment and at least a Grade D environment in the case of sterile productions (A in D closed system). The use of isolators can ensure a very high level of protection against the risk of product contamination and, at the same time, provide the operators with a very safe working environment. Furthermore, working with closed systems can optimize and facilitate the production of Advanced Therapy Medical Products in GMP environments, by providing an easily reproducible working tool even for large-scale production, with generally lower costs compared to a classical clean room approach. In conclusion, the isolator workstation as a possible alternative to the classic clean room, due to its small size and the simplification of the working and maintenance operational procedures, may represent an interesting solution in the perspective of the increasingly more stringent requests for cost reductions of GMP in clinical application.

Role of raw materials in biopharmaceutical manufacturing: risk analysis and fingerprinting.

Accurate fingerprinting of critical raw materials that have significant impact on process performance and product quality is a necessary precursor for implementation of QbD in process and product development. This article presents a review of major developments in this space in the last 10 years, with a special emphasis on those in last 5 years. A step by step approach for managing raw materials in the QbD paradigm has been proposed. We think that it is necessary for the biotech industry to better manage variability originating from raw materials if holistic implementation of QbD is to be achieved.

Integration of new technology into clinical practice after FDA approval.

Development of new medical technology is a crucial part of the advancement of medicine and our ability to better treat patients and their diseases. This process of development is long and arduous and requires a significant investment of human, financial and material capital. However, technology development can be rewarded richly by its impact on patient outcomes and successful sale of the product. One of the major regulatory hurdles to technology development is the Food and Drug Administration (FDA) approval process, which is necessary before a technology can be marketed and sold in the USA. Many businesses, medical providers and consumers believe that the FDA approval process is the only hurdle prior to use of the technology in day-to-day care. In order for the technology to be adopted into clinical use, reimbursement for both the device as well as the associated work performed by physicians and medical staff must be in place. Work and coverage decisions require Current Procedural Terminology (CPT) code development and Relative Value Scale Update Committee (RUC) valuation determination. Understanding these processes is crucial to the timely availability of new technology to patients and providers. Continued and better partnerships between physicians, industry, regulatory bodies and payers will facilitate bringing technology to market sooner and ensure appropriate utilization.

Molecular farming on the rise--GMO regulators still walking a tightrope.

Recent increases in EU commercial and academic activities in molecular farming, and the proximity to market-stage of the first plant-made pharmaceuticals, represent a call to action for EU regulators. Drawing on the North American debate on molecular farming, it will be argued that both the rationale and the risks of molecular farming will differ significantly from those of first generation GM crops. Based on these differences, the suitability of the existing regulatory frameworks, which were developed in response to the arrival of earlier products, is discussed, and specific options for adapting the already complex EU regulatory system to cater for molecular farming are examined.

El alcance del derecho a la vida en relación con el concebido según el Tribunal Europeo de Derechos Humanos

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Global herbal medicine: a critique.

Herbal medicine finds itself at a crossroads. If it continues to become mainstreamed in a commodity-driven health industry, its focus will change from craft-based tradition to globalized industry. On the other hand, if the fundamental importance of tradition to indigenous and nonindigenous medicine is respected, ecologic and cultural issues arise. Central here are the issues associated with control of both land and culture. Many indigenous cultures and their local ecologies are currently threatened by globalization. Historically, successful large corporations have neither respected the environment nor easily acknowledged indigenous claims to land and intellectual property, so no easy resolution of these conflicts seems likely. Our case study of Mapuche medicine allows us to explore the social and cultural conflicts that many practising herbalists experience. We argue that because of the basic contradictions involved, the protection of cultures and ecologies that underpin the discipline must be made a clear priority. We argue that local cultural traditions are clearly at odds with a globalizing herbal industry.

Environmental biotechnology: the ongoing quest.

Environmental biotechnology, until now, has primarily focused on the development of technologies to treat aqueous, solid and gaseous wastes. At present, the basic knowledge on how biotechnology can handle these wastes has been acquired and the focus is now on the implementation of these processes as 'best available technology not entailing excessive costs' (BATNEEC) in the framework of strict and transparent environmental legislation. New environmental challenges continue to evolve, as it becomes clear that waste streams should be tackled in an overall holistic way. New technologies to reach this goal are currently under development. Novel aspects with respect to the domain of water treatment are, for example, the biomembrane reactor technology and the newly discovered processes to remove nitrogen by means of anaerobic ammonium oxidation. Also, most challenging is the continuing strive for re-use of treated wastewater. Indeed, water shortage is emerging in an increasing number of countries all over the world and necessitates the short cycling of water. Finally, biotechnology has a key role to play in the novel approaches to design wastewater treatment based on decentralised sanitation and reuse (DESAR). Solid waste is a major challenge worldwide. The implementation of anaerobic digestion to treat biowastes has become a grown-up technology. New approaches in which biotechnological processes are linked to physical processes, such as plasma technology, certainly deserve special attention for the coming decades. Soil and sediment clean up by means of biostimulation/remediation/augmentation is now well established. Certainly, a number of prospects need to be further explored, such as the use of special energy sources to stimulate in situ the microbial community and the seeding of knowledge to the in situ community by means of horizontal gene transfer mechanisms. A number of waste gases can be handled by biofilter systems. Biological treatment of wastegases is also evolving, inasmuch as that besides conventional chemical pollutants, now also highly problematic chemicals (even dioxins) can be dealt with through proper biotechnological approaches. A remarkable new potential is the use of well designed probiotics to upgrade aquaculture and together with conventional biological water treatment processes, to guarantee the overall water quality of this domain of food production.

The role of the toxicologic pathologist in the preclinical safety evaluation of biotechnology-derived pharmaceuticals.

Biotechnology-derived pharmaceuticals, or biopharmaceuticals, represent a special class of complex, high molecular weight products, such as monoclonal antibodies, recombinant proteins, and nucleic acids. With these compounds, it is not appropriate to follow conventional safety testing programs, and the preclinical "package" for each biopharmaceutical needs to be individually designed. In addition to standard histopathology, the use of molecular pathology techniques is often required either in conventional animal studies or in in vitro tests. In this review, the safety evaluation of biopharmaceuticals is discussed from the perspective of the toxicologic pathologist, and appropriate examples are given of the use of molecular pathology procedures. Examples include the use of in situ hybridization to localize gene therapy vectors, the assessment of vector integration into genomic DNA by the polymerase chain reaction (PCR), and the use of immunohistochemistry to evaluate the potential cross-reactivity of monoclonal antibodies. In situ PCR techniques may allow for confirmation of the germ cell localization of nucleic acids and may therefore facilitate the risk assessment of germline transmission. Increased involvement with biopharmaceuticals will present challenging opportunities for the toxicologic pathologist and will allow for much greater use of molecular techniques, which have a critical role in the preclinical development of these compounds.